Interleukin-33 (IL-33), which is a member of the IL-1 superfamily of cytokines, is expressed predominantly by stromal cells, such as epithelial and endothelial cells, following pro-inflammatory stimulation. IL-33 is a ligand for ST2, a toll-like/interleukin-1 receptor super-family member that associates with an accessory protein, IL-1 RAcP (for reviews, see, e.g., Kakkar and Lee, Nature Reviews—Drug Discovery 7(10):827-840 (2008), Schmitz et. al., Immunity 23:479-490 (2005); Liew et. al., Nature Reviews—Immunology 10:103-110 (2010); US 2010/0260770; US 2009/0041718). Upon activation of ST2/IL-1 RAcP by IL-33, a signaling cascade is triggered through downstream molecules such as MyD88 (myeloid differentiation factor 88) and TRAF6 (TNF receptor associated factor 6), leading to activation of NFκB (nuclear factor-κB), among others.
IL-33 signaling has been implicated as a factor in a variety of diseases and disorders (Liew et. al., Nature Reviews—Immunology 10:103-110 (2010)). For example, while IL-33 is protective against helminth infection in a host and also reduces atherosclerosis by promoting TH2-type immune responses, it can also promote the pathogenesis of asthma by expanding TH2 cells and mediate joint inflammation, atopic dermatitis and anaphylaxis by mast cell activation. As such, IL-33 may be a new target for therapeutic intervention across a range of diseases; for example, blockade of IL-33 signaling may offer the potential to ameliorate multiple pathogenic features of certain inflammatory diseases.
IL-33 antagonists are described in U.S. Pat. Nos. 5,576,191; 7,666,622; 8,119,771; 8,187,596; 9,090,694; 9,212,227; 9,382,318; U.S. patent publication numbers 2007/0042978; 2009/0041718; 2010/0260770; 2012/0207752; 2012/0263709; 2014/0140954; 2014/0271642; 2014/0212412; EP patents or patent application numbers 1725261 B1; 2069784A1; 2152740A1; 2283860A2; 2475388A1; and PCT publication numbers WO05/079844; WO08/132709; WO08/144610; WO09/053098; WO11/031600; WO14/152195 and WO14/164959.
Calcitonin (CT) is a polypeptide hormone, thought to be produced primarily by parafollicular cells of the thyroid (Foster, G. V., et. al., (1964), Nature 202: 1303-1305). CT is a product of the CALCA gene, located on chromosome 11. The CALCA gene encodes the polypeptides procalcitonin (PCT) and PCT gene-related peptide α (proCGRPα), which are differentially expressed by alternative splicing (Christ-Crain, M. et. al. (2008), Crit Care Med 36:1684-1687; Hoff, A O, et. al. (2002), J. Clin. Invest. 110:1849-1857). Calcitonin (CT) is derived from a larger precursor, Procalcitonin (PCT, 116 amino acids), which is cleaved to immature calcitonin (33 amino acids) and then to mature calcitonin, a monomer of a 3.5-kd peptide composed of 32 amino acids. CT is predominantly produced by neuroendocrine cells such as C cells of the thyroid and pulmonary neuroendocrine cells (PNECs) by proteolytic cleavage in the secretory granules of producing cells before being released as mature CT polypeptide. Other cells that express the calca gene include mast cells, dorsal route ganglion cells (DRGs) and cells of the spinal cord. Multiple forms of circulating calcitonin precursors are found in the serum of healthy and diseased individuals (Becker K. et. al. (2004), J Clin Endocrinol Metab 89:1512-1525).
Calcitonin gene related peptide (CGRP) is a member of the calcitonin family of peptides. α-CGRP is a 37-amino acid peptide formed from the alternative splicing of the calcitonin/CGRP gene located on chromosome 11 (Amara, S G, et. al., (1982), Nature, 298 (5871): 240-244).
CT acts to reduce blood calcium, inhibits both osteoclasts and bone resorption, opposing the activity of parathyroid hormone (PTH) (Naot, D. and J. Cornish (2008), Bone 43(5): 813-818). In vivo and in vitro experiments suggest that the major physiological function of CT is to combat hypercalcemia in states of calcium stress such as during pregnancy, growth or lactation (Hoff, A. O., et. al., (2002), J Clin Invest 110(12): 1849-1857; Zaidi, M., et. al., (2002), J Clin Invest 110(12): 1769-1771). Diagnostically, CT is used as biomarker for medullary thyroid carcinoma (MTC). Normal circulating levels of CT peptides are low, however under physiological conditions these levels increase either systemically or locally. High CT levels indicate the presence of MTC and are used to evaluate the efficacy of surgical extirpation and recurrences. CT is also elevated in C-cell hyperplasia, pulmonary and pancreatic tumors, kidney failures and thyroid autoimmune disease (Becker, K. L., et. al., (2004). J Clin Endocrinol Metab 89(4): 1512-1525).
To date, no biomarkers for identifying patients that have, or are prone to develop an IL-33 mediated disease or disorder, or to determine a patient's likelihood to respond to therapy with an IL-33 antagonist have been identified. Although IL-33 antagonists have been identified that show promise in the treatment of inflammatory conditions, or allergies, biomarkers that may predict the efficacy of anti-IL-33 therapy are needed for the effective identification and selection of patient sub-populations that respond favorably to anti-IL-33 therapy. Accordingly, an unmet need exists in the art for identifying and validating predictive and prognostic biomarkers in patients with inflammatory conditions, or allergies, who are administered anti-IL-33 therapy.